Role of presympathetic neurons of the hindbrain in cardiovascular control

联系PD/PI：Abbott，Stephen 项目摘要 高血压是心血管疾病发展的重要危险因素。尽管主要 治疗进展，高血压往往是治疗抵抗，仍然导致无数人死于中风 和心脏病。高血压可能是神经源性的，即它与慢性高血压有关，并可能由慢性高血压引起。 交感神经活性（SNA）的升高。SNA的这种提高有许多可疑的原因，例如 增加颈动脉体活性、脑干低氧血症和CNS氧化应激，但 最终介导SNA提升的原因还不清楚。原因之一是我们对 连接和功能的大多数脑干通路参与SNA的产生。 这项建议的重点是A5组后脑去甲肾上腺素能神经元的贡献， 国民账户体系的监管， 血压（BP）。这一选择是出于四个方面的考虑。首先，A5神经元 是交感节前神经元去甲肾上腺素能输入的主要来源。第二，去甲肾上腺素 对交感神经节前神经元产生强大的兴奋作用。第三，A5神经元强烈地 因此可以介导缺氧对SNA的一些影响，并有助于 缺氧引起的适应性变化。最后，去甲肾上腺素代谢物从脑中流出， 高血压人（MHPG）的CNS NA释放升高，这表明CNS NA释放可能异常高。 这四个方面的考虑表明，A5神经元过度活跃可能有助于神经源性高血压。 我将检验A5去甲肾上腺素能细胞通过刺激交感神经系统来激活交感神经系统的假设。 交感神经节前神经元通过NA释放。其次，我建议确定转录组， 连接体的A5神经元，并将它们与邻近的神经元，控制血压的吻侧 延髓腹外侧最后，我将测试 A5依赖性NA释放 原因 交感 多动症 睡眠呼吸暂停（急性间歇性缺氧）模型。了解后脑网络 控制交感神经系统可有益于与交感神经系统相关的任何病症的治疗 功能障碍，如神经源性高血压、心力衰竭和多系统萎缩。 第6页 项目总结/摘要

Contact PD/PI: Abbott, Stephen Project summary Hypertension is an important risk factor for the development of cardiovascular disease. Despite major therapeutic advances, hypertension is often treatment resistant and still causes countless deaths from stroke and heart disease. Hypertension may be neurogenic i.e. it is associated with and probably caused by a chronic elevation of sympathetic nerve activity (SNA). This SNA elevation has many suspected causes such as an increase in carotid body activity, brainstem hypoxemia and CNS oxidative stress but the CNS network that ultimately mediates the SNA elevation is not well understood. One reason is our limited understanding of the connections and function of most brainstem pathways implicated in the generation of SNA. This proposal focuses on the contribution of the A5 group of hindbrain noradrenergic neurons to the regulation of SNA and blood pressure (BP). This choice is motivated by four considerations. First, A5 neurons are the main source of noradrenergic input to sympathetic preganglionic neurons. Second, noradrenaline exerts powerful excitatory effects on sympathetic preganglionic neurons. Third, A5 neurons are strongly activated by hypoxia and therefore could mediate some of the effects of hypoxia on SNA and contribute to the adaptive changes elicited by hypoxia. Lastly, the efflux of noradrenaline metabolites from the brain of hypertensive humans (MHPG) is elevated, which suggests that CNS NA-release may be abnormally high. These four considerations suggest that A5 neurons hyperactivity could contribute to neurogenic hypertension. I will test the hypothesis that A5 noradrenergic cells activate the sympathetic nervous system by exciting sympathetic preganglionic neurons via NA-release. Second, I propose to determine the transcriptome and connectome of A5 neurons, and compare them with that of neighboring neurons that control BP in the rostral ventrolateral medulla. And finally, I will test whether A5-dependent NA-release causes sympathetic hyperactivity in a model of sleep apnea (acute intermittent hypoxia). Understanding the hindbrain networks controlling the sympathetic system may benefit the treatment of any condition associated with sympathetic dysfunction, like neurogenic hypertension, heart failure and multiple systems atrophy. Page 6 Project Summary/Abstract